Genetics and Molecular Biology Parkinsonism

遗传学和分子生物学帕金森病

基本信息

批准号：
8134123
负责人：
DENNIS WILLIAM DICKSON
金额：
$ 11.63万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134123
关键词：
Achievement Administrator Advisory Committees Aging Alzheimer&apos s Disease American Americas Animal Model Animals Area Autopsy Award Biochemical Biological Assay Biological Markers Biological Models Book Chapters Boston Brain Calculi Case Study Cell Culture Techniques Cell Line Cell model Cells Cerebrovascular Disorders Chad China Chromosomes, Human, Pair 17 Cities Clinic Clinical Clinical Data Cognition Disorders Collaborations Collection Common Data Element Communities Complement Complication Consensus County Custom Cytopathology DNA Data Data Element Data Set Databases Dementia Development Diagnosis Diagnostic Disease Disease Association Doctor of Philosophy Drug Delivery Systems Drug Formulations Dystonia Education and Outreach Educational Activities Enrollment Eukaryotic Initiation Factor-4G Europe Evaluation Exclusion Criteria FTD with parkinsonism Faculty Family Fellowship Figs - dietary Follow-Up Studies Foundations Foxes Frontotemporal Dementia Funding Future Gene Expression Profile Gene Mutation Generations Genes Genetic Genetic Materials Genetic Screening Genome Genomics Germany Goals Grant Histologic Homologous Gene Hong Kong Human Human Cell Line Hypercapnic respiratory failure Impaired cognition Incidental Discoveries India Industry Institutes Institution Interdisciplinary Study International Internet Ireland Israel Japan Knowledge Korea LRRK2 gene Laboratories Lead Leadership Lewy Bodies Lewy Body Disease Link London Longitudinal Studies MPTP Poisoning Medical Medical Education Medical center Mental Depression Mentors Methods MicroRNAs Minnesota Mission Modeling Molecular Molecular Biology Molecular Diagnosis Molecular Genetics Motor Movement Disorders Multiple System Atrophy Mutation Names National Institute of Neurological Disorders and Stroke Neuroblastoma Neurodegenerative Disorders Neurologic Neurologist Neurology Northern Africa Norway Onset of illness Operon Outcome Paper Parkinson Disease Parkinson&apos s Dementia Parkinsonian Disorders Pathogenesis Pathologic Patient Education Patient Recruitments Patients Peer Review Pennsylvania Pharmacologic Substance Phenotype Phosphotransferases Play Poland Positioning Attribute Postdoctoral Fellow Preclinical Drug Evaluation Predisposition Principal Investigator Process Productivity Progress Reports Progressive Supranuclear Palsy Prospective Studies Protein Binding Domain Proteins Proteomics Publications RNA Interference Recruitment Activity Regulation Reporting Research Research Personnel Research Project Grants Research Proposals Resource Sharing Resources Rest Restless Legs Syndrome Risk Risk Factors Role SNCA gene Saimiri Sampling Scandinavia Scheme Scientist Series Services South America Spain Staging Students Subgroup Sum Support Groups Syndrome System Taiwan Targeted Research Testing Tetanus Helper Peptide Therapeutic Therapeutic Uses Time Toxic effect Training Translating Translational Research Travel Universities Variant Veins Washington Woman Work advanced disease alpha synuclein arm base brain research brain tissue candidate identification clinical material college comparative corticobasal degeneration cost effective cytotoxicity disability disorder risk dynactin early onset gene discovery genetic association genetic risk factor genetic variant genome wide association study genome-wide illness length improved infancy inhibitor/antagonist insight interest kindred leucine-rich repeat kinase 2 medical schools meetings member molecular pathology neuropathology neurosurgery next generation novel outreach population based posters pre-clinical pre-doctoral prevent programs prospective public health relevance skills small molecule small molecule libraries success therapeutic target viral gene delivery web page

项目摘要

DESCRIPTION (provided by applicant): The Udall Center for Excellence in Parkinson Disease Research at the Mayo Clinic is an integrated, multidisciplinary research program of neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the "Genetics and Molecular Biology of Parkinsonism." The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section and longitudinal studies of Parkinson disease (PD) and dementia with Lewy bodies (DLB) for the clinical material used in the research projects, as well as strong institutional commitment to PD research. The research proposed is highly synergistic despite the wide range of expertise and scientific background of the members of the Udall team. Each member of the team brings unique knowledge and skill sets to the mission, and together we are greater than the sum of the parts. The work proposed builds upon highly successful and productive cores that have been working together for over a decade. The clinical, genetic and pathologic resources are rivaled by few centers. The Mayo Udall Center is a unique complement to the Udall Center program. Success of our Udall Center has been based upon building successful collaborations and generous sharing of resources and data. This proposal has the overarching goal to better understand Lewy-related PD, which is the most common form of PD. Lewy bodies are also the hallmark of DLB and PD with dementia (PDD). How PDD and DLB relate to each other is unknown, but this non-motor complication of PD is of increasing interest to the Parkinson community. Strengths of our Udall Center are the large collection of multi-incident PD families, a proven track record of success in discovery of PD genes and a large collection of PD, PDD and DLB brains in a well annotated brain bank. The research proposal has three projects and five cores: Project 1. "Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD," (PL: Matthew J. Farrer, PhD); Project 2. "Identification of candidate therapeutics for a-synuclein aggregation and cytotoxicity," (PL: Shu-Hui C. Yen, PhD); Project 3. "Molecular pathology of Lewy-related cognitive dysfunction," (PL: Dennis W. Dickson, MD); Core A. Administrative (CL: Dennis W. Dickson, MD); Core B. Clinical (CL: Zbigniew K. Wszolek, MD); Core C. Genetic (CL: Matthew J. Farrer PhD); Core D. Neuropathology (CL: Dennis W. Dickson MD) and Core E. Education and Outreach (CL: Ryan J. Uitti, MD). PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is one of the leading causes of neurologic disability. Understanding its cause through genetic studies will lead to animal and cell culture models to develop treatments for PD. With advances in therapies for motor abnormalities in PD, there is increasing interest in understanding non-motor features of PD, including dementia, which is a focus of research. PROJECT 1 Principal Investigator: Matthew J. Farrer, Ph.D. Title: Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD Description (provided by applicant): Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center; it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 & 3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods. Public Health Relevance: Novel Parkinson disease (PD) genes identified by this Project in families with PD will provide a window into the cause of PD. Since a-synuclein is the major protein abnormality in PD, a comprehensive study of variability in the gene for a-synuclein will lead to new future therapies for PD.

描述（由申请人提供）：梅奥诊所的尤德尔帕金森病研究卓越中心是一个由神经学家、神经心理学家、遗传学家、神经病理学家和基础科学家组成的综合性多学科研究项目，研究“帕金森病的遗传学和分子生物学” ”。该中心利用梅奥诊所运动障碍科的临床优势以及帕金森病 (PD) 和路易体痴呆 (DLB) 的纵向研究作为研究项目中使用的临床材料，以及对 PD 研究的坚定机构承诺。尽管 Udall 团队成员拥有广泛的专业知识和科学背景，但拟议的研究具有高度的协同作用。团队的每个成员都为任务带来了独特的知识和技能，我们的共同努力大于各个部分的总和。拟议的工作建立在十多年来非常成功和富有成效的核心基础上。临床、遗传和病理资源很少有中心可以匹敌。梅奥尤德尔中心是对尤德尔中心计划的独特补充。我们尤德尔中心的成功建立在成功合作和慷慨共享资源和数据的基础上。该提案的总体目标是更好地了解路易相关帕金森病，这是最常见的帕金森病形式。路易体也是 DLB 和 PD 伴痴呆 (PDD) 的标志。 PDD 和 DLB 之间的关系尚不清楚，但帕金森社区对 PD 的这种非运动并发症越来越感兴趣。我们 Udall 中心的优势在于拥有大量多发 PD 家族、在发现 PD 基因方面的成功记录以及在注释良好的脑库中收集了大量 PD、PDD 和 DLB 大脑。该研究提案包含三个项目和五个核心：项目 1：“识别预测帕金森病发病、易感性和进展的遗传风险因素”（PL：Matthew J. Farrer 博士）；项目 2.“α-突触核蛋白聚集和细胞毒性候选疗法的鉴定”（PL：Shu-Hui C. Yen 博士）；项目 3.“路易相关认知功能障碍的分子病理学”（PL：Dennis W. Dickson，医学博士）；核心 A. 行政（CL：Dennis W. Dickson，医学博士）；核心 B. 临床（CL：Zbigniew K. Wszolek，医学博士）； Core C. Genetic（CL：Matthew J. Farrer 博士）；核心 D. 神经病理学（CL：Dennis W. Dickson 医学博士）和核心 E. 教育和外展（CL：Ryan J. Uitti，医学博士）。公共卫生相关性：帕金森病 (PD) 是神经系统残疾的主要原因之一。通过遗传学研究了解其病因将有助于建立动物和细胞培养模型来开发帕金森病的治疗方法。随着帕金森病运动异常治疗的进展，人们对了解帕金森病的非运动特征越来越感兴趣，包括痴呆症，这是研究的焦点。项目1 首席研究员：Matthew J. Farrer 博士标题：预测帕金森病发病、易感性和进展的遗传风险因素的识别描述（由申请人提供）：我们过去的尤德尔中心申请（2004-2009）的工作提供了令人信服的遗传、基因组和生化证据，表明野生型α-突触核蛋白的过度表达是路易体病的主要危险因素。过去的基因发现立即改善了罕见家族的诊断，并引发了行业赞助的针对α-突触核蛋白基因的RNA干扰转化项目。然而，我们的（PD、PDD、DLB 和 MSA）以及α-突触核蛋白的作用还处于起步阶段。项目 1 有四个目标来解决这些问题：目标 1 对患有临床帕金森病和尸检证实路易体病的多事件家庭进行外显子测序。正如我们的初步数据所示，所使用的方法提供了一种快速且具有成本效益的方法来识别疾病中的新基因突变。目标 2 是对非突触核蛋白病进行全面的 SNCA 基因组捕获和重新测序，以便能够对一系列路易体疾病的临床和病理表型进行比较遗传关联研究。我们需要确定影响疾病风险的精确变异及其分子机制。目标 3 中的工作使用特征最好的样本的子集，将提供来自 α-突触核蛋白病全基因组转录组分析的补充数据。最后，目标 4 将描述内源 miRNA 在调节 α-突触核蛋白表达中的作用。该项目无法在中心之外完成；它在很大程度上依赖于核心 B、C 和 D 提供的资源和专业知识，并将相互为项目 2 和 3 中的研究提供信息。我们的目标是提供有意义的分子诊断，以对这一异质性疾病组进行重新分类。我们的目标是通过基因发现，以及利用下一代测序方法的进步，提供对路易体疾病发病机制的机械理解，以及α-突触核蛋白及其同系物的发病机制。公共健康相关性：本项目在帕金森病家族中发现的新帕金森病 (PD) 基因将为了解帕金森病的病因提供一个窗口。由于α-突触核蛋白是帕金森病中的主要蛋白质异常，因此对α-突触核蛋白基因变异性的全面研究将带来未来帕金森病的新疗法。